17alpha-cyclopropyltestosterones



United States Patent Ofifice Patented May 9, 1967 3,318,924 17a-CYCLOPROPYLTESTOSTERONES Vlasios Georgian, Belmont, Mass, assignor to Trustees of Tufts College, Medford, Mass, a corporation of .Massachusetts N Drawing. Filed Jan. 6, 1965, Ser. No. 423,821 8 Claims. (Cl. 260397.4)

This invention relates to novel l7-substituted testosterone derivatives and more specifically to 17a-cyclopropyltestosterones. These compounds have anabolicandrogenic, anti-inflammatory and hypocholesteremic activity.

The compounds of this invention may be represented by the following general structural formula:

l H O OH O H If If Oppenauer H oxidation 0:

In a second method, a 4-androstene-3,l7-dione is converted to a 3-enamine derivative .by treatment with pyrrolidine or morpholine in for example a methanolic, ethanolic or acetone solution which is then similarly reacted with lithium cyclopropylbromide. The resulting 17a-cyclopropyl substituted S-enamine is then cleaved by heating with a mixture of acetic acid, methanol and so- .dium acetate to give the 17a-cyclopropyltestosterone derivative.

This method may be illustrated by the following reaction sequence:

5C3 ID F 1) Li, -Br

(2) AcOH, MeOH, AcONa.

The compounds of Formula I wherein Y is a double bond are advantageously prepared by oxidation of the 17a-cyclopropyltestosterones with preferably dichlorodicyanoquinone.

The compounds of Formula I where R is an acyl group are prepared by reacting the 17a-cyclopropyltestosterone derivative with the corresponding acid anhydride.

The following examples illustrate the methods of preparation described above but are not intended to limit the scope of this invention.

Example 1 Lithium metal (1.38 g.) in 25 ml. of anhydrous ether is treated with 12.1 g. of cyclopropylbromide diluted with 10-20 ml. of anhydrous ether. The resulting solution is stirred for one hour andrefiuxed one hour. The ether is removed by distillation and replaced with anhydrous tetrahydrofuran. To this solution is added dropwise 5.76 g. of dehydroepiandrosterone in ml. of tetrahydrofuran and the mixture is refluxed for 12 hours. The excess lithium metal is cautiously destroyed with several milliliters of cold methanol in an ice-bath and the reaction mixture is poured into water. The aqueous phase is slightly acidified with dilute hydrochloric acid and the solid material is collected and dried. The aqueous phase is also extracted with methylene chloride to isolate additional product. The total crude product is purified by passage through a Florisil column in 10% methanol-methylene chloride solution to yield 17a-cyclopropyl-5-androstene-3fi,l7,8-diol, M.P. 176-178 C.

Example 2 A solution of 4.5 g. of l7a-CYClOplOPYl-S-flIldIOStenc- 3;8,17,8-diol (prepared as in Example 1) in 400 m1. of toluene is azeotroped to dryness and then is treated with 4.3 g. of aluminum isopropoxide and 21.6 ml. of distilled cyclohexanone. The mixture is refluxed for 30 minutes with slow distillation of toluene. The hot solution is treated dropwise with water and the filtered toluene phase is steam distilled for three hours. The resulting aqueous phase is extracted with methylene chloride, dried and evaporated to give an oil which crystallizes, 17a-cyclopropyltestosterone, Ml. 158159 C.

Example 3 Following the general procedures of Examples 1 and 2 an employing equivalent amounts of reactants,

1 1 fl-hydroxydehydroepiandrosterone, 6-methyldehydroepiandrosterone and 1ofi-methyldehydroepiandrosterone are converted by reaction with lithium cyclopropylbromide to the corresponding 17a-cyclopropyl-5-androstene-3 {3,1 1,6,175triol, 17a-cyclopropyl-6-methyl-5-androstene-3,8,17fi-diol, and 17x-cyclopropyl-16/3-methyl-5-androstene-3{3,17fi-diol which in turn are oxidized under Oppenauer conditions to yield, respectively,

17a-cyclopropyll-androstene-11,8,17fl-diol-3-one, 17 wcyclopropyl-Ga-methyltestosterone, and 17 xcyclopr0pyl-16fl-rnethyltestosterone.

Oxidation of 17a-cyclopropyl-4-androstene-11fi,17f3-diol- 3-0ne With chromic acid in acetone gives l7a-cyclopropyl- 4-androstene-3,1 1-dione-17-ol.

Example 4 To a solution of 0.46 g. of 9a-fluoro-11fl-hydroxy-4- androstene-3,17-dione in 3 ml. of methanol near reflux under nitrogen is added 0.2 ml. of pyrrolidine. The solution is cooled and filtered to give 3(N-pyrrolidinyl)-9ufiuoro-l1fi-hydroxy-3,5androstadiene-17-one.

Lithium metal (0.69 g.) in 15 ml. of anhydrous ether is treated with 6.0 g. of cyclopropylbromide diluted with 10-20 ml. of anhydrous ether. After one hour reflux, the ether is removed by distillation and replaced with anhydrous tetrahydrofuran. To this solution is added dropwise 3.9 g. of the above 3-(N-pyrrolidinyl)-androstadiene in 100 ml. of tetrahydrofuran and the mixture is refluxed for 12 hours. The excess lithium metal is cautiously destroyed with several milliliters of cold methanol.

To the reaction mixture is then added a buffer solution consisting of 12 g. of sodium acetate in 40 ml. of water, 16 ml. of glacial acetic acid and 175 ml. of methanol. The mixture is refluxed for 30 minutes, cooled, diluted with water and extracted with chloroform. The chloroform extract is washed with dilute hydrochloric acid, then with sodium carbonate solution, finally with water, dried and evaporated to yield 17ot-cyclopropyl-9m-fluoro-4-androstene-l1;8,17fl-diol-3-one.

Example Following the general procedure of Example 4 and employing equivalent amounts of reactants,

712-111fithYl-4-3HdIOStGI1C-3 17-dione, 6 8-methyl-1l[i-hydroxy-4-androstene-3,17-dione, and 2a-methyl-1 1,8-hydroxy-4-androstene-3 ,17-di0ne are converted to the corresponding 3-(N-pyrrolidinyl) enamine derivatives, reacted with lithium cyclopropylbromide to give the 17a-cyclopropyl-3-(N-pyrrolidinyl)- enamines which are cleaved with sodium acetate, acetic acid and methanol buffer to yield, respectively,

17e-cyclopropyl-7a-methyltestosterone, 17a-cyclopropyl-6a-methyl-4-androstene-115,17,8-diol 3- one, and '17a-cyclopropyl-2u-methyl-4-androstene-1 113, 17/3-di0l-3- one.

Example 6 A mixture of 1.0 g. of 17a-cyclopropyltestosterone (prepared as in Example 2), 0.8 g. of dichlorodicyanoquinone and ml. of dioxane is refiuxed with stirring for two hours. The reaction mixture is cooled, diluted with ether and the hydroquinone filtered and Washed with ether. The filtrate is concentrated in vacuo to give 17w cyclopropyl-l,4-androstadiene-17-ol-3-one.

Example 7 ORA P A #12 wherein:

Y is a member selected from the group consisting of a 1,2-single bond and a 1,2-double bond;

R is a member selected from the group consisting of hydrogen and acyl derived from a lower aliphatic carboxylic acid of from 2 to 4 carbon atoms;

R is a member selected from the group consisting of hydrogen, hydroxy and keto;

R is a member selected from the group consisting of hydrogen and fiuoro; and

R R R and R are members selected from the group consisting of hydrogen and methyl.

2. A chemical compound of the formula:

gig Q 3. A chemical compound of the formula:

4. A chemical compound of the formula:

5 6 5. A chemical compound of the formula: 7. A chemical compound of the formula:

OH H E i O l 5 R1- R3 Q i HO O=C 10 R4 wherein:

R is a member selected from the group consisting of hydrogen and hydroxy; and

R and R are members selected from the group consisting of hydrogen and methyl.

8. A chemical compound of the formula:

15 6. A chemical compound of the formula:

83 A OH No references cited.

30 LEWIS GOTTS, Primary Examiner.

wherein R is acyl derived from a lower aliphatic car- ELBERT L. ROBERTS, Examiner.

boxylic acid of from 2 to 4 carbon atoms.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,318,924 May 9, 1967 Vlasios Georgian t error appears in the above numbered pat- It is hereby certified the hat the said Letters Patent should read as ent requiring correction and t corrected below.

Column 5 lines 18 to 28 for that portion of the formula readlng OH read (JR Signed and sealed this 15th day of October 1968 (SEAL) Attest:

EDWARD J. BRENNER Edward M. Fletcher, Jr.

Commissioner of Patents Attesting Officer 

1. A CHEMICAL COMPOUND OF THE FORMULA: 